Crystalline form of JAK kinase inhibitor bisulfate and a preparation method thereof

Abstract

A crystal form of JAK kinase inhibitor bisulfate and a preparation method thereof are provided. In particular, a type II crystal of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate and a preparation method thereof are described. The preparation method includes steps of crystallizing any solid crystal form or amorphous compound of formula (I) in a single organic solvent or a mixed organic solvent to obtain a type II crystal form of the compound of formula (I). The type II crystal form of the compound of formula (I) obtained by the described methods has good crystal stability and chemical stability. In addition, the solvent used for crystallization has low toxicity and residue, which is better suited for use in clinical treatment.

What is claimed is: 
     
       1. A crystal form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate, wherein the crystal has a characteristic X-ray powder diffraction (XRPD) spectrum comprising diffraction peaks at angles (2θ±0.2°) of 9.06, 11.91, 15.09, 18.31, 20.93, 22.16, 22.62, 23.03, and 27.14. 
     
     
       2. The crystal form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate according to  claim 1 , wherein the crystal has a differential scanning calorimetry (DSC) spectrum comprising an endothermic melting peak at about 217.24° C. 
     
     
       3. A pharmaceutical composition comprising the crystal form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate according to  claim 1  and at least one pharmaceutically acceptable carrier. 
     
     
       4. The pharmaceutical composition according to  claim 3 , having an amount of the crystal form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate of 0.5 mg to 200 mg. 
     
     
       5. The pharmaceutical composition according to  claim 3 , wherein the pharmaceutically acceptable carrier is selected from at least one of lactose, mannitol, microcrystalline cellulose, croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl methyl cellulose, povidone, and magnesium stearate. 
     
     
       6. A preparation method of the crystal form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate according to  claim 1 , comprising the following steps of:
 (a) dissolving any crystal form or amorphous form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide in an organic solvent to obtain a mixture, then adding concentrated sulfuric acid dropwise to the mixture to precipitate the crystal form, or adding an anti-solvent to the mixture to precipitate the crystal form; 
 or dissolving a solid of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate in any crystal form or amorphous form in an organic solvent under heating, then cooling the solution to precipitate the crystal form, 
 wherein the organic solvent is selected from the group consisting of alcohols, ketones, esters having 3 or less carbon atoms, or a mixed solvent thereof, and a halogenated hydrocarbon having 3 or less carbon atoms; and 
 (b) filtering the crystal form, then washing and drying it. 
 
     
     
       7. The preparation method according to  claim 6 , wherein the organic solvent in step (a) is methanol, ethanol, isopropanol, acetone, ethyl acetate, a mixture of dichloromethane and methanol, a mixture of dichloromethane, methanol and ethanol, a mixture of dichloromethane, methanol and isopropanol, a mixture of dichloromethane, methanol and ethyl acetate, or a mixture of dichloromethane, methanol and acetone. 
     
     
       8. The preparation method according to  claim 7 , wherein the organic solvent is methanol or a mixture of dichloromethane, methanol and ethanol. 
     
     
       9. The preparation method according to  claim 8 , wherein the organic solvent has a ratio of dichloromethane:methanol:ethanol of about 12:3:10. 
     
     
       10. An isolated crystal form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate, wherein the crystal has a characteristic X-ray powder diffraction (XRPD) spectrum comprising diffraction peaks at angles (2θ±0.2°) of 9.06, 11.91, 13.23, 13.64, 14.00, 14.53, 15.09, 16.64, 18.31, 18.86, 19.26, 19.83, 20.93, 22.16, 22.62, 23.03, 23.69, and 27.14. 
     
     
       11. An isolated crystal form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate, wherein the crystal has an X-ray powder diffraction (XRPD) spectrum as shown in  FIG. 1 . 
     
     
       12. A pharmaceutical composition comprising the isolated crystal form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate according to  claim 10  and at least one pharmaceutically acceptable carrier. 
     
     
       13. A pharmaceutical composition comprising the isolated crystal form of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate according to  claim 11  and at least one pharmaceutically acceptable carrier. 
     
     
       14. A method of inhibiting a Janus kinase (JAK) in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of  claim 3 . 
     
     
       15. The method according to  claim 14 , wherein the subject is in need of treatment of rheumatic arthritis or rheumatoid arthritis. 
     
     
       16. A method of inhibiting a Janus kinase (JAK) in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of  claim 12 . 
     
     
       17. The method according to  claim 16 , wherein the subject is in need of treatment of rheumatic arthritis or rheumatoid arthritis. 
     
     
       18. A method of inhibiting a Janus kinase (JAK) in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of  claim 13 . 
     
     
       19. The method according to  claim 18 , wherein the subject is in need of treatment of rheumatic arthritis or rheumatoid arthritis.